PROJECT SUMMARY/ABSTRACT Hepatitis B (HBV) coinfection in HIV is common in resource-limited settings (RLS). Antiviral therapy can be effective in the prevention of mother to child transmission (PMTCT) of HBV and the WHO recommends antiretroviral therapy (ART) with dual HBV activity with tenofovir (TDF)/emtricitabine (FTC) or lamivudine (3TC) in HIV/HBV coinfection. ART with 3TC alone as the sole HBV active agent may also be considered. 3TC alone results in HBV resistance and a vaccine escape phenotype while TDF may be associated with maternal and infant morbidity. Despite the use of these HIV PMTCT regimens in areas endemic for HBV, it is unknown how these agents will impact HBV outcomes. The long-term goal of our program is to identify the optimal PMTCT strategy in HIV/HBV coinfection. The objective here is to determine whether an antepartum regimen with TDF/FTC is superior to a regimen with 3TC. Our central hypotheses are that dual HBV therapy with TDF/FTC will be superior to single HBV therapy in virologic outcomes but may not be superior with regards to maternal and infant safety, that HBV clinical outcomes will be worse without ART, and that HIV/HBV women will have worse outcomes, compared to HBV uninfected women. The rationales are that, if TDF is associated with greater morbidity among infants and if 3TC is associated with little HBV drug resistance, then there may be a role for short-course 3TC alone in HIV/HBV infected pregnant women. These findings would help inform WHO guidelines. If ART cessation is associated with clinically important adverse outcomes, then HBV mono- infection guidelines would need re-consideration. Finally, if HIV/HBV women have worse outcomes compared to HIV mono-infection then we need to identify interventions to address these adverse outcomes. These central hypotheses will be tested using the plasma repository of the Promoting Maternal and Infant Survival Everywhere (PROMISE) study, an HIV PMTCT trial of 3500 mother-infant pairs in which a pre-planned HBV substudy randomized HIV/HBV coinfected women to three antepartum strategies; ART with single (zidovudine (ZDV)/3TC/Lopinavir/ritonavir (LPV/r), dual (TDF/FTC/LPV/r), and no HBV active therapy (ZDV, intrapartum single dose nevirapine, and TDF/FTC tail). We will pursue three specific aims: 1) Compare HBV virologic outcomes in HIV/HBV women and their infants among randomized arms, 2) Compare clinical hepatic outcomes in HIV/HBV women among randomized arms, and 3) Compare maternal and infant clinical outcomes between HBV infected and uninfected women and their children, among randomized arms. Using a novel next generation sequencing (NGS) assay, the evolution and role of HBV minority variants and their association with HBV transmission will be examined. The approach is innovative because it will change how HBV PMTCT regimens are selected and because it will utilize a novel NGS assay that has several advantages over current techniques. The proposed research is significant because it will define the optimal PMTCT regimen in HIV/HBV coinfection. Such knowledge will inform global HBV public health prevention strategies.